P674: 2ND-LINE PONATINIB IN CHRONIC PHASE CHRONIC MYELOID LEUKEMIA (CML-CP) PATIENTS FAILING OR INTOLERANT TO 1ST-LINE 2ND GENERATION TKI THERAPY: INTERIM ANALYSIS OF THE PROSPECTIVE PONS TRIAL
Authors: Philipp Le Coutre, Joachim Göthert, Susanne Saussele, Uwe Pelzer, Lars Bullinger, Ahmet Elmaagacli, Christian Jehn, Frank Stegelmann, Andreas Hochhaus, Thomas Ernst, Andreas Burchert
Journal: HemaSphere (2023)

Background: Ponatinib at a daily dose of 45 mg is an orally available TKI approved for patients failing or not tolerating 1st and 2nd line therapy in CML-CP. Although ponatinib showed robust response rates in CML-CP patients highly resistant and intolerant to 2nd generation TKIs it was not recommended for earlier lines of therapy in the past primarily due to cardiovascular toxicities. The OPTIC trial demonstrated durable efficacy and improved safety with a response based dose adjustment strategy, starting with 45 mg and reducing to 15 mg upon achievement of ≤1% BCR-ABL1 (Cortes et al.: Blood. 2021;138:2042-50). Aims: The primary endpoint was rate of MMR by 12 months of ponatinib. The aim was also to capture all cardiovascular events. Methods: In the present PONS study (NCT03807479), we exclusively investigated ponatinib starting with 30mg/d in 2nd line and mostly after 2nd generation TKI. To prospectively capture treatment related cardiovascular events, patients were monitored with echocardiography, duplex or ankle brachial index of lower extremities, blood sugar metabolism and fundoscopy at baseline and 12 weeks. Dose escalation in patients not responding up to 45 mg was allowed. Results: A total of 22 patients were screened and 18 (14 male and 4 female) were enrolled from Dec 2018 until Jan 2022, including ten resistant and eight intolerant patients to first line TKI treatment. At baseline the median age was 43.6 years (range, 20 to 79). Prior to therapy with ponatinib only one (5.5%) patient was in MMR, eight (66.6%) were in CCyR (complete cytogenetic remission) and two (16.65%) were in MCyR (major cytogenetic remission). First line treatments were imatinib (n = 3), dasatinib (n = 9), or nilotinib (n = 6). The median duration of ponatinib treatment was 14.5 months (2.4 – 26.3). In 17 patients the starting dose of ponatinib was 30 mg/d. For interim analysis, response and toxicity data of months 3 and 12 (n = 18 pts) were analyzed. One patient showed data consistent with lymphatic blast crisis at baseline but was kept on study. After 3 months, 7 (58.3 %) patients with available cytogenetics analyses were in CCyR, 6 (33.3 %) in MMR and 3 (16.7 %) in MR4 or better. After 12 months 7 (58.3%) patients were in CCyR, 7 (38.9%) in MMR and 4 (22.2%) in MR4 or better. At the time of this analysis (data cut 01. Jun 2022) all patients were alive and one patient progressed to advanced CML. Currently, 6 patients are still under treatment, 4 are past end of study treatment, 4 discontinued treatment due to adverse events, 1 failed to achieve a CHR at months 3, 2 were switched to an alternative treatment and 1 because of protocol deviation. Toxicity data at month 3 showed a total of 86 AEs (all grades) with 15 considered as grade 3/ 4. Of these 15 AEs 3 were hematological and 12 were non-hematological. Grade I/II cardiovascular AEs were hypertension (n=6), coronary artery disease (n=1) and stent implantation (n=1). Only 1 grade 3 cardiovascular event (aphasia) occurred. Data on toxicity prevention including echocardiography, duplex or ankle brachial index of lower extremities, blood sugar metabolism and fundoscopy will be presented. Summary/Conclusion: In patients failing first line second generation TKI therapy with nilotinib or dasatinib, we observed robust responses and fewer cardiovascular events in patients treated with a reduced dose of ponatinib. Importantly, strict preventative measures of cardiovascular risk factors may reduce the occurrence of such AEs, providing durable disease control. Table 1: Cytogenetic and molecular response rates of 2nd line ponatinib in CP CML patients - Baseline Month 3 Month 12 CCyR (N = 12) 8 (66.6 %) 7 (58.3 %) 7 (58.3 %) MMR (N = 18) 1 (5.5 %) 6 (33.3 %) 7 (38.9 %) MR 4 (N = 18) 0 3 (16.7 %) 4 (22.2 %) Keywords: Chronic myeloid leukemia